Previously, we reported global hypermethylation in DS might be attributed to the overexpression of HSA21 gene DNMT3L, which can enhance DNMT3A and DNMT3B activities in DNA methylation. To test this hypothesis, we compared the DNA methylation and RNA expression profiles of early-differentiated human neuroprogenitors with and without DNMT3L overexpression. We found DNMT3L overexpression only moderately increased the DNA methylation of limited genes, yet significantly altered global RNA expression of genes involved in neural differentiation. We further found that DNMT3L bound STAT1 or STAT3, and increased its phosphorylation and nuclear translocation, which in turn activated the expression of transcription factors including HES3, ASCL1, NEUROD2 and NEUROG2 and CDK inhibitor CDKN1A, which promoted cell cycle exit and neural differentiation. This phenomenon was also confirmed in Dnmt3l conditional knockin mice, which could be rescued by STAT1 and STAT3 phosphorylation inhibitors (Fludarabine and SH-4-54) but not DNA methylation inhibitor (Decitabine). These results suggest that DNMT3L play an important role during neurodevelopment independent of DNA methylation, which may contribute to the abnormal phenotypes observed in Down syndrome cortex.Voltage-gated sodium channels (Navs) 1.7, 1.8, and 1.9 are predominately expressed in peripheral sensory neurons and are critical for action potential propagation in nociceptors. Unexpectedly, we found that expression of SCN9A, SCN10A, SCN11A, and SCN2A, the alpha subunit of Nav1.7, Nav1.8, Nav1.9 and Nav1.2, respectively, are up-regulated in spinal dorsal horn (SDH) neurons of miR-96 knockout mice. These mice also have de-repression of CACNA2D1/2 in DRG and display thermal and mechanical allodynia that could be attenuated by intrathecal or intraperitoneal injection of Nav1.7 or Nav1.8 blockers or Gabapentin. Moreover, Gad2CreERT2 conditional miR-96 knockout mice phenocopied global knockout mice, implicating inhibitory neurons; nerve injury induced significant loss of miR-96 in SDH GABAergic and Glutamatergic neurons in mice which negatively correlated to up-regulation of Nav1.7, Nav1.8, Nav1.9 and Scn2a, this dis-regulation of miR-96 and Navs in SDH neurons contributed to neuropathic pain which can be alleviated by intrathecal injection of Nav1.7 or Nav1.8 blockers. In conclusion, miR-96 is required to avoid allodynia through limiting the expression of VGCCs and Navs in DRG and Navs in SDH in naïve and nerve injury-induced neuropathic pain mice. Our findings suggest that central nervous system penetrating Nav1.7 and Nav1.8 blockers may be efficacious for pain relief.The subiculum serves as the strategic core output of the hippocampus, through which neural activity exits the hippocampal proper and targets the entorhinal cortex and other more distant subcortical and cortical areas. The past decade has witnessed a growing interest in the subiculum, owing to discoveries revealing its critical role in regulating many physiological and pathophysiological processes. Notably, accumulating evidence from both clinical and experimental studies suggests that the subiculum plays a vital role in seizure initiation and propagation, in epilepsy. In this review, we briefly describe the structure and connectivity of the subiculum and then summarize the molecular and cellular mechanisms in the subiculum underlying the epileptic brain, in both epilepsy patients and animal models. Next, we review some translational approaches targeting the malfunctioned subiculum to treat epilepsy. Finally, we pose open questions for future research in the subiculum and their clinical translation challenges.
  Reduction in L-type Ca
  current (I
  ) density is a hallmark of the electrical remodeling in atrial fibrillation (AF). The expression of miR-155, whose predicted target gene is the α1c subunit of the calcium channel (CACNA1C), was upregulated in atrial cardiomyocytes (aCMs) from patients with paroxysmal AF.The study is to determine miR-155 could target the gene expression of I
  and contribute to electrical remodeling in AF.
 
  The expression of miR-155 and CACNA1C was assessed in aCMs from patients with paroxysmal AF and healthy control. I
  properties were observed after miR-155 transfection in human induced pluripotent stem cell derived atrial cardiomyocytes (hiPSC-aCMs). Furthermore, an miR-155 transgene (Tg) and knock-out (KO) mouse model was generated to determine whether miR-155 was involved in I
  -related electrical remodeling in AF by targeting CACNA1C.
 
  The expression level of miR-155 was increased, while the expression level of CACNA1C reduced in the aCMs of patients with AF. miR-155 transfection in hiPSC-aCMs produced changes in I
  properties qualitatively similar to those produced by AF. miR-155/Tg mice developed a shortened action potential duration and increased vulnerability to AF, which was associated with decreased I
  and attenuated by an miR-155 inhibitor. Finally, the genetic inhibition of miR-155 prevented AF induction in miR-155/KO mice with no changes in I
  properties.
 
  The increased miR-155 expression in aCMs was sufficient for the reduction in the density of I
  and the underlying electronic remodeling. The inhibition of miR-155 prevented I
  -related electric remodeling in AF and might constitute a novel anti-AF approach targeting electrical remodeling.
 The increased miR-155 expression in aCMs was sufficient for the reduction in the density of ICa,L and the underlying electronic remodeling. The inhibition of miR-155 prevented ICa,L-related electric remodeling in AF and might constitute a novel anti-AF approach targeting electrical remodeling.One of the complexities of understanding the pathology of familial forms of cardiac diseases is the level of mutation incorporation in sarcomeres. Computational models of the sarcomere that are spatially explicit offer an approach to study aspects of mutational incorporation into myofilaments that are more challenging to get at experimentally.  https://www.selleckchem.com/products/ms023.html  We studied two well characterized mutations of cardiac TnC, L48Q and I61Q, that decrease or increase the release rate of Ca2+ from cTnC, k-Ca, resulting in HCM and DCM respectively [1]. Expression of these mutations in transgenic mice was used to provide experimental data for incorporation of 30 and 50% (respectively) into sarcomeres. Here we demonstrate that fixed length twitch contractions of trabeculae from mice containing mutant differ from WT; L48Q trabeculae have slower relaxation while I61Q trabeculae have markedly reduced peak tension. Using our multiscale modelling approach [2] we were able to describe the tension transients of WT mouse myocardium. Tension transients for the mutant cTnCs were simulated with changes in k-Ca, measured experimentally for each cTnC mutant in whole troponin complex, a change in the affinity of cTnC for cTnI, and a reduction in the number of detached crossbridges available for binding.